Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can cause premature deaths. If an individual is known to be predisposed, clinical management can be initiated to prevent these deaths. We and others have determined that up to 20% of TAAD patients without a genetic syndrome have a family history of TAAD (FTAAD). We estimated that the known genes for FTAAD account for disease in approximately 30% of FTAAD families. We have established a cohort of FTAAD families (620 families with two or more members affected by TAAD), which has been used to map, identify, and confirm 13 FTAAD genes and establish the clinical phenotype associated with each gene. We hypothesize that there are multiple genes responsible for disease in the remaining families. The overarching goal of the project is to identify the remaining genes for FTAAD, characterize the phenotype associated with novel genes, perform initial studies linking the mutant gene to aortic disease, and rapidly translate these findings into improved clinical care and prevention of premature deaths in FTAAD families. The aims of the project are the following: (1) recruit and characterize additional FTAAD families, along with families with genetically triggered TAAD, to be used to identify novel genes and delineate the clinical features and mutation spectrum associated with these genes; (2) use linkage data and whole exome and genome sequencing of affected relatives and trios to efficiently identify rare variants in novel FTAAD genes; (3) perform initial pathologic, molecular and cellular biology studies of novel FTAAD genes; (4) pursue case control association studies for single rare variants and variants aggregated within a gene to identify novel FTAAD genes. In summary, we are uniquely poised to identify novel FTAAD genes based on our assembled cohort and preliminary data indicating that we can identify novel genes for FTAAD. Uncovering FTAAD genes is crucial for identifying individuals at risk for aortic dissections and initiating gene-specific clinical management, as well as understanding the causal mechanisms of inherited thoracic aortic disease.